A Rare Case of Clear Cell Sarcoma of the Tongue: A Case Report

Clear cell sarcoma (CCS), previously known as soft tissue melanoma due to similarities with melanoma, is a rare and aggressive neoplasm. This tumor predominantly occurs in the lower limbs and rarely affects the tongue, as well as other head and neck locations. To our knowledge, only five cases have been reported in the English literature. CCS presents many similar morphological and immunohistochemical features to those of melanomas, sarcomatoid cell carcinoma, angiomatoid histiocytoma, and Ewing sarcoma, which makes the diagnosis difficult, especially in cases of uncommon locations. The treatment is based on oncological surgery and adjuvant radiation therapy as these tumors show low sensitivity to chemotherapy. This study aimed to report a case of an 88-year-old male patient who presented a large, rapidly growing nodular lesion on the right border of the mobile tongue diagnosed with CCS of the tongue.


Introduction
Clear cell sarcoma (CCS), previously known as soft tissue melanoma, is a rare and aggressive tumor that preferentially occurs in the lower extremities of young adults [1].CCS arising in the tongue is extremely rare [2].To our knowledge, only five cases of tongue CCSs have been reported in English literature.The term soft part melanoma is because CCS shares many similarities such as the expression of melanocytic markers.The most important distinguishing features between the two entities are the presence of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in melanomas and their absence in CCS.In addition, CCS is characterized by the presence of rearrangement of Ewing sarcoma breakpoint region 1 (EWSR1), whereas it is absent in melanomas [3,4].
As an uncommon entity, its diagnosis can be difficult, relying on histological and molecular findings.CCS exhibits a characteristic nested or fascicular architecture with epithelioid to plump spindled cells partitioned by thin fibrous septa.It typically shows a notably infiltrative growth pattern through dense fibrous tissue.

Case Presentation
An 88-year-old male patient presented with a large, rapidly growing nodular lesion on the right border of the mobile tongue within three months.The patient had a history of diabetes mellitus under oral antidiabetics, arterial hypertension under therapy, and no history of alcohol and tobacco abuse.
Oral cavity examination revealed the presence of a large, focally ulcerated nodular lesion, measuring 4 cm x 3 cm x 1 cm with a firm consistency, and the presence of many fibrinous deposits on the surface of the lesion (Figure 1).No cervical lymphadenopathies were clinically found.The patient underwent a large resection of the lesion (Figure 2).The pathological assessment revealed a nested proliferation of large, epithelioid, clear, and eosinophilic cells showing prominent nucleoli and vesicular chromatin.Nests of tumor cells were separated by fibrous septa (Figures 3-4).Many foci of perineural invasions were observed.Only three mitoses per 10 high-power fields could be identified.The resection margins were free of proliferation.The immunohistochemical study showed expression of S100, HMB-45, SOX10, and vimentin and no expression of melanoma antigen-A (Melan-A), epithelial membrane antigen (EMA), cytokeratin, p63, CD86, or CD45 (Figure 5).Fluorescent in situ hybridization revealed the presence of EWSR1 and ATF1 gene fusion.
The patient underwent adjuvant radiotherapy.Further investigations revealed no distant locations and no metastatic lymphadenopathies.The six-month follow-up indicated favorable progress, with no reported recurrences or metastases in the patient.

Discussion
CCS is a rare sarcoma of soft tissue.The name melanoma of soft parts was given to this entity following the identification of melanocytic differentiation.The melanocytic differentiation has been identified at the ultrastructural level by the presence of melanosomes and at the immunohistochemical level by the identification of expression of melanocytic markers such as HMB-45, S100, microphthalmia-associated transcription factor (MITF), tyrosinase, and Melan-A [5].
More classical locations for CCS include deep soft tissue of the distal extremities, especially the lower limbs.Additionally, it may occur in the proximal extremities, trunk, and, rarely, the skin [11].This latter location is well documented, although some cases of cutaneous CCS can result from the extension of deep-seated lesions [12].
The occurrence of CCS is extremely rare in the head and neck region, and it occurs even rarely in the tongue, with, to our knowledge, only five reported primary cases of CCS in the tongue documented in the English literature (Table 1).CCS of the tongue, similar to most reported cases of mucosal CCS of the head and neck region, tends to occur in young patients.It exhibits a distribution regarding sex and age similar to that observed in deep soft tissue cases [8].
Clinically, the tumor most commonly presents as a slowly growing mass in the deep soft tissue.Mucosal CCS can sometimes be mistaken for a benign lesion such as a case of gingival CCS mistaken for an odontogenic abscess in a 17-year-old girl [8].For mucosal CCS, such as CCS of the tongue, since it tends to be superficial, the diagnosis can be made relatively early in the stage of small lesions.In our reported case, the lesion was large as it was neglected by the patient.
Morphologically, a nested proliferation with numerous fibrous septa is often observed.The cells are large and epithelioid, featuring clear to eosinophilic cytoplasm with prominent nucleoli and vesicular chromatin [8].
At the immunophenotypic level, CCS cells show a diffuse expression of S100 protein and SOX10 and frequently show expression of melanocytic markers (HMB-45, Melan-A, Mel-CAM, and MiTF) [8].
Molecular biology is often necessary for a positive diagnosis, especially to distinguish it from melanoma [13].
Fluorescent in situ hybridization (FISH) enables the identification of the EWSR1 gene fusion with the ATF1 gene, secondary to the translocation t(12;22) (q13; q12).FISH enables confirmation of diagnosis in 70% of CCS cases.Molecular biology study also includes the identification of EWSR1-ATF1 fusion transcripts by reverse transcription polymerase chain reaction (RT-PCR).It is positive in more than 90% of CCS cases [14,15].
Many entities are included in the differential diagnosis.The most important and challenging diagnosis remains melanoma, particularly its nodular variant.This is noteworthy because nodular melanoma appears to be overrepresented in the head and neck region, with an incidence of 20%, compared to 12% in other sites [7,15].In addition, the diagnosis can be morphologically more challenging in cases of nodular melanoma lacking a radial growth phase, therefore showing only a nested pattern as that present in CCS cases.
Similarly, nodular melanoma cases with clear cell change add more difficulties to the diagnosis [16].It is worth mentioning that even though rare, CCSs with a junctional component exist and may be easily confused with the diagnosis of melanoma [3].Immunohistochemical features cannot help distinguish these two entities since they both express the same melanocytic markers.In addition to melanoma, other melanocytic lesions could be confused with CCS such as cellular blue nevus and perivascular epithelioid cell neoplasm (PEComa).
The gastrointestinal neuroectodermal tumor (GNET) is another important entity to include in the differential diagnosis.It is a rare tumor that occurs in the small intestine, stomach, or colon wall with morphological overlap with features of CCS.However, this neoplasm does not express melanocytic markers [17,18].
Despite the many overlapping features between the two entities, the pathologist should pay attention to some distinguishing features such as the presence of osteoclast-like giant cells and the more pleomorphic aspect of the nuclei, two elements that are suggestive of the diagnosis of GNET since cases of CCS show more monotonous cells and classically no osteoclast-like giant cells.Immunohistochemistry plays a key role in distinguishing between CCS and GNET since GNET classically lacks expression of melanocytic markers.
On the molecular level, GNET shows rearrangement of the EWSR1 gene; however, fusion does occur with the CREB1 gene and not with the AATF1 gene (as in the case of CCS) [8].However, EWR1-CREB1 fusions have been documented in 6.3% of CCS.
While the rearrangement of EWSR1 helps obtain a definitive diagnosis in most cases of CCS, it is not specific to this entity and is reported in an increasing number of soft tissue tumors that can present in the head and neck region.These include angiomatoid fibrous histiocytoma, Ewing sarcoma, and myoepithelioma of soft tissue [19].
Other differential diagnoses include sarcomatoid squamous cell carcinoma, which is highly aggressive.The diagnosis can be oriented by expression of high-molecular-weight cytokeratin, p63, and p14.Other sarcomas that may be confused with CCS are cited in Table 2, with the respective immunohistochemical stain that should be used to retain or exclude them [8].The main treatment of CCS in its classical location, as well as for those located on the tongue, remains based on surgical resection.The overall five-year survival rate is approximately 50%-60%, with factors such as tumor necrosis and a size greater than 50 mm being indicators of bad prognosis.A long-term follow-up is necessary as cases of recurrence and distant metastases have been reported [19].

Conclusions
CCS is a rare and aggressive soft tissue tumor.It occurs preferentially in deep soft parts of the lower limbs in young adults.Primary tongue CCS is extremely rare.Many entities are included in the differential diagnosis of CCS, including the challenging melanoma, especially in its nodular form, as both entities express melanocytic markers and show the presence of melanosomes at the ultrastructural level.Molecular biology is often necessary to establish a definitive diagnosis, especially in uncommon locations such as the tongue, which enables identification of t(12;22) (q13; q12) with secondary EWSR1-ATF1 fusion.The treatment is based on surgery followed by a long-term follow-up, as recurrences and distant metastases have been reported in cases of treated CCS.

FIGURE 1 :
FIGURE 1: The tongue nodular lesion: a large, 4 cm x 3 cm x 1 cm focally ulcerated lesion, with the presence of many fibrinous deposits on the surface.

Human subjects:
Consent was obtained or waived by all participants in this study.Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.